Approximately 30% of diffuse large B cell lymphomas (DLBCLs) co-express high levels of Myc and Bcl2 proteins (Myc+/Bcl2+ DLBCL), which confers a poor prognosis when treated with standard chemotherapy regimens. Accordingly, Myc+/Bcl2+ expression defines a subset of patients with DLBCL with a clear unmet medical need. The goal of this project is to develop novel mechanism-based therapy to improve the cure rate of patients with Myc+/Bcl2+ DLBCL. To do that, we will capitalize on the recent knowledge reported by our group and others demonstrating oncogenic cooperation between Myc and Bcl2, and Myc and activated PI3K pathway that can be exploited by novel targeted approaches. As the development of drugs that can directly inhibit Myc protein remains challenging, we will examine alternative approaches, including targeting Myc transcription using HDAC inhibitors and bromodomain inhibitors, or Myc translation using inhibitors of mTORC1 and the eIF4A RNA helicase. In Aim 1, we will investigate the contribution of protein translation to Myc/Bcl2 expression In DLBCL. In Aim 2, we will perform preclinical experiments to develop novel mechanism-based treatment strategies for Myc+/Bcl2+ DLBCL. In Aim 3, we will conduct phase I/II studies of novel therapies developed from Aims 1 and 2 to evaluate their safety and efficacy in patients with Myc+/Bcl2+ DLBCL.